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Oral contraceptive use and mortality after 36 years of follow-up in the Nurses’ Health Study: prospective cohort study

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"These results pertain to earlier oral contraceptive formulations with higher hormone doses rather than the now more commonly used third and fourth generation formulations with lower estrogen doses."
Recent evidence from long term observations of hundreds of thousands of women, in 10 European Countries, clearly demonstrated that the use of oral contraceptives reduced mortality by roughly 10%. Despite all thromboembolism risks, apparently.
Reference
doi: 10.1186/s12916-015-0484-3.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627614/

We read a recent paper by Charlton et al.1 with great interest. The authors investigated the association between oral contraceptive (OC) use and mortality, and demonstrated an increased rate of mortality for breast cancer as well as a decreased rate of mortality for ovarian cancer.1 These opposite findings regarding the association between OC use and the cancer mortality are of interest. We also read additional prior papers2,3 that reported that OCs could protect against ovarian cancer while also increasing the risk of breast cancer, which appear to support the findings obtained by Charlton et al.1 However, these previous studies, including the paper by Charlton et al.,1-3 do not completely explain the biological mechanisms underlying the effects of OC use on the incidence of cancer. Elucidating such mechanisms may help to produce strategies for preventing cancer induced by OCs. In general, OCs are thought to prevent ovulation, thereby suppressing the development of ovarian cancer, while OCs (estrogen and progestin) also promote the proliferation of cells, including cancer cells.1

In this context,1-3 little has been mentioned regarding the oxidative stress burden with respect to the development of breast cancer, although oxidative stress is generally associated with carcinogenesis. We previously reported that OC use may increase the levels of derivatives of reactive oxygen metabolites, which can be used to measure the overall oxidative stress burden by analyzing the oxidation of various components, such as lipids, proteins and nucleic acids.4 The level measured with this test is positively correlated with the level of C-reactive protein, a marker of chronic inflammation, and also OC use reportedly increases the C-reactive protein level.5 Therefore, we would like to propose a possible involvement of OS and inflammation in the development of breast cancer, in particular, as a partial explanation for the above findings.1-3

Among the various types of cancer, why is breast cancer more frequently associated with oxidative stress and inflammation? As for ovarian cancer, are the effects of ovulation suppression by OCs on the development of ovarian cancer greater than those of oxidative stress and inflammation induced by OCs? Even though such questions remain, the link between oxidative stress and inflammation and the onset of breast cancer associated with OC use would be an attractive research topic when paying special attention to recent data regarding OC use.4,5 Further studies on the issues of oxidative stress and inflammation are warranted to clarify the mechanisms underlying these findings.1-3

The Nurses’ Health Study (NHS) is arguably the most famous and influential observational cohort study ever. Investigators have published more than1000 articles on the NHS, at a rate of more than 50 papers/year for the last 10 years.1 30% of the publications were published in journals with impact factors greater than 10, and 15% were published in one of the 6 most prestigious general medicine journals (Annals of Internal Medicine, Archives of Internal Medicine, BMJ, Lancet, JAMA, New England Journal of Medicine).1 To date, more than 2000 hypotheses have been tested in these papers,1 and it seems likely that the number of statistical tests carried out would be in the tens of thousands. As with this paper, the majority of the statistically significant associations are weak (relative risk 0.5-2.0):1 associations of this size in observational studies are likely to be spurious.2

Given the volume of hypotheses assessed and statistical tests undertaken, it seems likely that many results reported in NHS publications are false positives, and that the use of a threshold of P=0.05 for statistical significance is inappropriate without consideration of multiple statistical testing.

We suggest that authors of observational studies should report how many hypotheses have been tested previously in their cohort study, together with an estimate of the total number of statistical tests undertaken. This information should then be used to estimate the likelihood of false positive results in the current publication. It would be valuable to see this information for the current NHS article.

This study is seriously flawed. It sets out to compare mortalities in two groups of women. Those who took oral contraceptives and those who did not. The key issue is: what age were these women, and what age did they die at? The reason age is crucial is because oral contraceptives cause a disproportionate number of deaths in young women. So if you measure deaths at older ages you will nullify this effect in the statistics and actually may end up coming to absolutely unfounded and dangerous conclusions. The Cancer Research UK website is worth visiting. It shows that 32% of cancer deaths in women aged 25 to 49 years were due to breast cancer. It shows that only 16% of female cancer deaths in those aged 50 to 74 years were due to breast cancer. How do you expect to detect breast cancer deaths due to oral contraceptives when the mean age of participants at mid point (1994 see table 1) was 61 years? This means that the mean age at intake in 1976 was 42 years. This means that a significant number of breast cancer deaths due to oral contraceptives had already occurred and were missed. It also means that the contraceptive breast cancer connection is seriously diluted and made negligible, by the rising causes of death in women aged 60 to 78 years which is the last half of the study age range. This is fairly basic isn't it? In order to study an effect you see when the effect happens and you capture it. You don't see when it happens and avoid it ....or do you?

Competing interests:
I have written a short journalistic monograph on why female hormones increase the incidence of breast cancer. It is "The Screech Owls of Breast Cancer" available online.

The authors of the Nurses’ Health Study added hormone therapy (HRT) users to both Ever and Never users of oral contraceptives. This seriously underestimates the increased mortality from taking hormones for contraception.1

Only 13.7% of women (16,670 / 121,577) are listed as Never users of oral contraceptives or HRT. What would their results show if just these 16,670 women were used as controls?

It is nonsense to standardise for the use of similar or identical hormones given for different reasons. All oral contraceptives, and HRT combinations which are given to women with a uterus, act predominantly like progesterone to avoid oestrogen induced endometrial hyperplasia and endometrial cancer.2 Progesterone is a more powerful breast mitogen than oestrogen.3 Percentage increases and decreases in breast cancer incidences have matched changes in use of progestogens since 1962. Figure 1

It is also misleading to believe that oral contraceptives can prevent ovarian cancer. Progestogens and oestrogens given as HRT increase ovarian cancer incidence and mortality.4

Progestogens and low doses of oestrogens cause depression and loss of libido with matching increases in monoamine oxidase activities.5 Even this flawed study found increase in mortality from accidents and violence and suicide especially in the first year of oral contraceptive use which is when many women with headaches, depression and weight gain stop further use. However, in my experience residual effects can be increased sensitivity to yeasts, more food allergies and nutritional deficiencies, impaired gut absorption with decreased secretion of pancreatic enzymes and increased bacterial and fungal fermentation. I have been treating post pill patients for decades to prevent further repeated miscarriages and “unexplained” infertility and depression.

It is wrong to claim that mortality does not differ between women who had ever used oral contraceptives and never users. Progestogens can increase the risk of breast cancer and fatal vascular diseases and depression within one year of use.